Final Report Summary - SILENT HIV (Paving the way toward HIV eradication/control)
Human Immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, is a retrovirus that primarily infects cells of the immune system. The outcome of HIV-1 infection results from complex interactions between viral proteins and host cell factors. In most cases, HIV-1 successfully hijacks cellular pathways and bypasses cellular restriction factors for optimal replication leading to continuous rounds of infection, replication and cell death. Ongoing viral replication causes the loss of CD4+ T cells and progression to immunodeficiency in infected individuals. However, in certain situations, virus replication can be successfully controlled. First, HAART (Highly Active AntiRetroviral Therapy) treatment revealed the existence of a pool of resting memory CD4+ T cells harbouring integrated but silent HIV-1 provirus. Although this situation occurs in a small number of cells, it suggests that intracellular defence mechanisms can be effective against HIV. This long lived viral reservoir is believed to be the major obstacle against HIV-1 eradication by HAART (Marcello, 2006). Second, HIV-infected individuals who are able to control their virus to undetectable levels for many years in the absence of any treatment have been identified and referred to as Elite HIV controllers “EC”. Again, this is a rare situation observed in 0.5% of infected patients. Still, it demonstrates that it is possible to naturally and effectively control HIV replication and disease progression. A common feature of these two situations is that virus replication is controlled at the gene expression level. A major challenge in the HIV field is to understand how these naturally occurring situations where intracellular defence and/or immune response win the battle against HIV. Our objectives were to identify the host factors and define the molecular mechanisms involved in the regulation of HIV-1 gene expression and to explore the involvement of cellular microRNA in virus replication. We were able to identify the key cellular factors required for viral gene expression and shown their contribution to HIV transcriptional silencing. Importantly, we identified the cellular factors that dictates the permissiveness of cells to HIV. Particularly, we were able to determine why resting CD4 T cells and dendritic cells are non-permissive to HIV.